Abstract

Mammalian cells encode three D cyclins (D1, D2, and D3) that coordinately function as allosteric regulators of cyclin-dependent kinase 4 (CDK4) and CDK6 to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation, and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclin D2 or D3 in human cancers, and as such, it has been more extensively characterized. Overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signaling, bypass of key cellular checkpoints, and ultimately, neoplastic growth. This review discusses cyclin D1 transcriptional, translational, and post-translational regulations and its biological function with a particular focus on the mechanisms that result in its dysregulation in human cancers.

Ubiquitin Proteasome-mediated cyclin D1 Degradation. Phosphorylation is the first step for cyclin D1 degradation. GSK-3β phosphorylates cyclin D1 at Thr-286. After phosphorylation, cyclin D1 is transported from nucleus to cytoplasm, where it is recognized by different E3 ligases, including Fbxo4, Fbxo31, Fbxw8, β-TrCP and APC/C. After polyubiquitylation, cyclin D1 1s targeted to proteasome for degradation.